Synthesis of substituted imidazoles



Patented Feb. 13, 1951" SYNTHESIS OF SUBSTITUTED IMIDAZOLES Reuben G. Jones, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of lndiana N Drawing. Application September 17, 1948, Serial No. 49,863

' 7 Claims. (01. 260-309) 1 My invention relates to the preparation of substituted imidazoles and more particularly to a process of preparing 2-mercapto-5-carboxyimidazole esters.

The imidazole nucleus is found in a number of biologically important substances, among which are compounds such as histamine, histadine, alantoin and pilocarpine. All of thesecompounds are characterized by the presence of 'substituents in the 5-position of the imidazole nucleus. Methods for the preparation of 5-substituted imidazoles are known. However, the general methods hitherto known to the art involve many tedious steps and are productive of low yields of imidazoles.

It is an object of my invention to provide a simple and convenient method of synthesizing 2-mercapto-5-carboxyimidazole esters which are useful as intermediates in the synthesis of imidazoles having substituents in the 5-position. Other objects will be apparent from the following disclosure.

In fulfillment of the above and other objects, I' have provided a synthesis of 2-mercapto-5- carboxyimidazole esters, which comprises condensing a C-formylglycine ester with a thiocyanate.

The reaction between the C-formylglycine ester enol and the thiocyanate leading to the production of the 2-mercapto-5-carboxyimidazole esters may be represented by the following equation:

wherein R represents hydrogen or an alkyl,

"sition, or substituted by a group such as a methyl, hexyl, propyl, cyclohexyl, cyclopentenyl, phenyl, benzyl or phenethyl group.

In the practice of my invention, one method of procedure compri'ses'mixing in aqueous solution approximately equivalent molecular quantities of the C-formylglycine ester enol with hydrogen thiocyanate, i. eQthiocyanic acid. An equivalent procedure employs water-soluble metal salts of one or both of the reactants, and the carrying out of the reaction in the presence of a strong,

The intermediates used in my novel synthesis can be obtained by methods known to the art. Thiocyanic acid and its water-soluble salts are, of course, well known. The C-formylglycine ester enols are known as a class of compounds and can be synthesized in several ways. For the purposes of illustration, a method of synthesis of C-formylglycine ester enols which may be represented by the following formula 5 RzON0COOR1 o UHOH wherein R, Rrand R2 have the same significance as before, is outlined below: An inorganic acid salt of a primary amine containing the desired R substituent is treated in aqueous solution with formaldehyde and potassium cyanide to produce an aminoacetonitrile wherein the amino group bears the R substituent. The substituted aminoacetonitrile is hydrolyzed to the corresponding carboxylic acid and the acid is esterified in the 3 glycine ester having a formyl, acetyl or propionyl radical as the acyl group. The acylated este is C-formylated with methyl formate and alkali in benzene according to the method of Claisen [Ann 337, 236 (1904)], yielding an alkali metal enolate salt of a C-formylglycine ester. The metal enolate salt of the glycine ester can be isolated by adding several volumes of ether to the benzene solution and filtering off the solid enolate salt. The salt, so prepared, can be preserved for some time before employing it in my synthesis. It desired, the enolate salt ne'ed not be isolated but may be extracted with water from the benzene solution in which it is prepared, and the aqueous solution employed in my reaction. The free enol can be prepared from the salt by acidifying an aqueous solution of the salt and extracting the enol from the aqueous solution with a water-immiscible solvent such as chloroform. I H h The reactions involved in the above describe'd' preparation of the C-formyl glycine ester enols may be represented by the following equations in which R, R1 and lit; have the same significance as heretofore and M represents a metal which forms a water-soluble salt with the glycine ester enol.

The conditionsunder which thec-formylglycine ester enol is condensedwith .thetthiocyan-ateare notcritical. Alsolvent is employed, and preferably thesolvent is an: aqueous solvent such as water or aqueous alcohol which contains a sufiicient amount of .waterto retain insolution any inorganic salt which may be produced in the reaction, as for example when one or both 4 The following examples further illustrate my invention.

EXAMPLE 1 Preparation of 1-i$opropyl-2-mercapt0-5-carbomethoryimidaeole 1 isopropyl 2 mercapto 5 carbomethoxyimidazole represented by the formula HC--CCOOOHa may be prepared in the following manner:

The enolate of N-formyl-N-isopropyl-C-formylglycinemethyl ester used in preparing l-isopropyl 2 mercapto 5 carbomethoxyimidazole isprepared as follows: 191 g. (2 mols) of isopropylamiho hydrochloride and 250 cc. of 40 percent Formalin are dissolved in 100 cc. of water, and while the mixture is cooled in an ice bath and continuously stirred, there is added in portions over a period of about two hours, a cold concentrated aqueous solution of 130 g. (2 mols) of potassium cyanide. During this time the tempera-ture is kept below 10 C. and the mixture is kept in a carbon dioxide atmosphere, by adding Dry Ice to the solution from time to time. The mixture is; stirred for one additional hour and is then extracted WithtWo 500 cc. portions of ether. The combined ether extracts are dried over calcium oxide and theether removed by evaporation in vacuo. The residue, comprising isopropylaminoacetonitrile, is dissolved in 2.5 liters of dry methanolsaturated in the cold with hydrogen chloride. The resulting solution is allowed to stand atroom temperature for about 10 hours and is then heated under reflux for four hours. The ammonium chloride which separates is filtered ofiandthe filtrate is evaporated in vacuo to obtain crude N -isoproplyglycine methyl ester hydrochloride, The crude ester hydrochloride is dissolved in 250cc, of 98 perc'entformic acid. vTo this solution is added a hot solution of 150 g. of sodiumformate in 200' cc, of 98 percent formic acid. After the mixture has stood for about an hour, the precipitatedsodium of the principal reactants is in the form of a water-soluble metal salt; The presence of a relatively large proportion of water in the aqueous solvent is also of assistance in the isolation of the 2 -mercapto-5-carboxyimidazo1e ester which has a relatively low solubility in water.

Efreferably the condensationis carried out at a temperature above temperature (i. e. 20 C.) in order to expedite the rate at which the reaction proceeds. Temperatures between about C. and 100 C. are most desirable, but the condensation may be carried out satisfactorily despite substantial departures from this temperature range.

As noted above, when a water-soluble salt of one or both of the principal reactants is employed, a strong acid is used to produce the acid form of the reactants. The acid used may be of any strong, non-oxidizing mineral acid such as hydrochloric, hydrobromic, phosphoric acid and the' like.

chloride is filtered of? and 450 cc. of acetic anhydride are added to the filtrate in portions. After the vigorous reaction has subsided the mixture is heated for about 30 minutes ona steam bath to csmplete the; regaiction. The formic and acetic acids present in the reaction mixtureare removed by evaporation in vacuo and the residue, comprising the acylated ester, istreated with one liter of acetone whereupon a further quantity of 's'odiiirfi chloride'separates. The sodium chloride is filtered e-fi; the acetone is removed from the filtrate by evaporation in vacuo and the residue is fractionally distilled in vacuo. N-formyl-N-isopropylglycine methyl ester boils at about 9l-92 C. at 1.5 mm. pressure.

Analysis of the e's't'er'h-a s Shown the presence of 8.67 percent nitrogen as compared with the calculated 8.80 percent.

The sodium enolate salt of the N'formyl--N- isopropyl-C-formylglycine methyl ester is prepared by the Claisen method. A mixture of 106 g. (0.67 mol) of N formyl' N isopropylglycine methyl ester and g. (2.0 mols) of dry methyl formate is cooled in an ice bath and a suspension of 40 g. (Q.7 1 mol) of sodium methoxi'de in 15f) cc. of anhydrous benzene is added in 5' perti'ons, with continuous stirring, over a period of about one hour. The temperature of the reaction mixture is maintained below 15 C. and stirring is continued for about one hour after all of the sodium methoxide has been added. The reaction mixture is then allowed to stand in the refrigerator for about 24 hours. The sodium enolate salt is precipitated by the addition of 500 cc. of anhydrous ether. The precipitate is filtered off, washed with anhydrous ether and dried in vacuo.

140 g. (0.67 mol) of the sodium enolate salt of N formyl N isopropyl C formylgycine methyl ester are dissolved in 500 cc. of water. While the solution is kept cold in an ice bath, 127 cc. (1.52 mol) of 12 N hydrochloric acid are added, and the solution is treated with 83.5 g. (1.03 mol) of sodium thiocyanate. The reaction mixture is removed from the cooling bath and heated for 45 minutes at about 90 C. The mixture is allowed to stand for a few hours at room temperature 'to aid crystallizationof the l-isopropyl 2 mercapto 5 carbomethoxyimidazole which is formed in the reaction. The mixture is then cooled to about C., whereupon the 1 isopropyl 2 mer-capto- 5 carbomethoxyimidazole formed in the reaction is substantially completely precipitated. The crystalline precipitate is filtered off, washed with cold water and dried. About 125 g. (93 percent of the theoretical amount) of 1-isopropyl-2-mercapto-5- carbomethoxyimidazole are obtained.

-isopropyl 2 mercapto 5 carbomethoxyimidazole thus prepared melted at 148-149 C.

Analysis showed the presence of 13.61 percent nitrogen as compared with the calculated amount of 13.99 percent.

EXAMPLE 2 1 -isopropy1- 2 mercapto 5 carbomethoxyimidazole may also be prepared as follows:

The sodium salt of N-formyl-N-isoDropyl-C- formylglycine ester prepared as described in Example 1 is converted to its acid form by dissolving the sodium enolate salt in a minimum amount of ice cold water, acidifying the solution with hydrochloric acid and repeatedly extracting the aqueous solution with chloroform. The combined chloroform extracts are dried over magnesium sulfate and the chloroform is removed by evaporation under reduced pressure leaving as a residue the N-formyl-N-isopropyl-C-formylglycine ester. 7

EXAMPLE 3 Preparation 0 1-methyl-2-mercapto-5-carbomethoxyimidazole 1 methyl 2 mercapto 5 carbomethoxyimidazole represented by the formula no 0-0 0 0 one 7 N i TCHs is prepared'as follows;

A suspension of the sodium salt of N-formyl- N-methyl-C-formylglycine methyl ester in benzene is prepared according to the method set out in Example 1, except that methylamine is used instead of isopropylamine. The benzene suspension is extracted several times with cc. portions of cold water to obtain the sodium enolate salt in aqueous solution. An aqueous extract thus obtained and which contains about 350 g. of N-formyl-N-methyl-C-formylglycine methyl ester is cooled to about 0 C. and treated with 450 cc. (5.4 mols) of 12 N hydrochloric acid. Immediately thereafter 226 g. (2.8 mols) of crystalline sodium thiocyanate are added and the mixture is removed from the coolingbath and heated for 45 minutes at 90 C. After standing a few hours at room temperature, the reaction mixture is cooled to about 0 C. to cause complete precipitation of the 1-methyl-2-merca'pto 5-carbomethoxyimidazole from solution. The precipitate is filtered oif. The yield of l-methyl- 2-mercapto-5-carbomethoxyimidazole is 300 g. (72 percent of theory) 1 methyl 2 mercapto 5. carbomethoxyimidazole thus prepared melted at l93-194 C.

EXAMPLE 4 Preparation of Z-mercapto-5-carbethomyimidazole 2-mercapto-5-carbethoxyimidazole represented by the formula HC=(? CO0O2H5 N NH may be prepared as follows:

395 g. (3 mols) of N-formylglycine ethyl ester prepared from glycine ethyl ester by the general method set out in Example 1, and 670 g. (9 mols) of anhydrous ethyl formate are dissolved in 700 cc. of anhydrous benzene and cooled in an ice bath. A suspension of 220 g. (3.25 mols) of sodium ethylate in 500 cc. of anhydrous benzene is added, with stirring, in five portions over a period of one hour. The stirring i continued for another hour and the mixture is then placed in a refrigerator at 10 C. for about 48 hours.

The cold mixture, which contains a suspension of the, sodium salt of N-forrnyl-C-formylglycine ethyl ester, is extracted several times with cold water. The water extracts which contain the sodium enolate salt are combined and treated with 550 cc. (6.6 mols) of 12 N hydrochloric acid. 350 g. (3.6 mols) of potassium thiocyanate are added and the resulting mixture is heated for about 45minutes at C. The reaction mixture is allowedtd stand at room temperature for a few hours and is then cooled'in an ice bath, whereupon 2 mercapto 5 carbethoxyimidazole precipitates. The precipitate is filtered 01f and dried. The yield of 2-mercapto-5-carbethoxyimidazole melting at about 184 C. is about 280 g. (54 percent of theory) Analysis of 2-mercapto-5-carbethoxyimidazole thus prepared showed the presence of 42.03 percent carbon and 4.99 percent hydrogen as com pared with the calculated values of 41.84 percent carbon and 4.68 percent hydrogen,

600cc. of 50 percent ethanol-water. .lution are added 154 cc. (1.85 mol) of 12 N hy- 7 EXAMPLE 5.

Preparation of 1,-cyclohezvyl2=mercapto.-5 earbor methoqryimidazole l-- cyclohexyl 2 mercapto carbomethoxyimidazole 1 represented by the" formula isgpreparedv as. follows:

18.6;g. (0.75 mol) of the sodium enolate salt vof;N formyl N cyclohexyl C formylglycine methyl ester, prepared b starting with cyclohexyl .amine in accordance with the general method set forth in Example 1, are dissolved in Tothis sooff, washed with cold water and dried. The yield of 1 cyclohexyl-.2-mercapto:5-carbomethoxyimidazole is 178g. (98 percent of theory).

1 cyclohexyl 2 mercapto 5 carbomethoxyimidazolethus,preparedmelts at 1'71-1'72 C.

Analysis showed the presence of. 11.56 percent nitrogen as compared with the calculated amount of 11.66 percent;

EXAMPLE 6 Preparation of 1 benzyl 2 mercapto 5 carbomethoxyimidazole 1 benzyl 2 mercapto 5 carbomethoxyimi-dazole represented by the formula is prepared as. follows:

.220 g. (0.86 mol) of the sodium enolate salt of N-formyl-N-benzyl-C-forrnylglycine methyl ester prepared fromloenzylamineinaccordance withthe generalmethod setforth in Example 1, are dissolved in 700 cc. of 50 percent ethanolwater. 165 cc. (2 mols) of 12 N hydrochloric acid are added while cooling'the solution. in an ice-salt mixture, and the cooled. solution is treated with 110 g. (1.35 mol) .of sodium :thi'ocyanate. The mixtureis heated for about. an hour at 99 C. and is then allowedto stand at room temperature for a 'few hours. Upon cooling the mixture inan ice-salt bath, l-bemyl- 2 mercapto 5 carbomethoxyimidazole pre-- cipitates. The precipitate, is filtered. off',.. washed with cold water and dried. The yieldv is 206%. (9''! percent of theory) 1 benzyl 2 mercapto 5:--carbomethoxyimidazole thusprepared melts at about..174 1'75 C. Analysisadisclosed the. presence of 58 percent .carbon and. 4.88 percent. hydrogen, as compared, with the -calculatedamounts .01. 58.04 percent and 4.87 percent. respectively.

8 EXAMPLEL'Z Preparation of 1 a-naphthyhz mercaptod-carbobutozryimidazole 1 a.-- naphthyl 2 mercapto- 5 carbobutoxyimidazolerepresented by the formula .nozcaoo OZOIH iscprepared.v according to the'procedure ofExam- .p1e.,1, from sodium' thiocyanate and the sodium .salt of ,tlie.C-,formy1 derivativeof N-a-naphthyl- .N+formylglycine butyl ester.

The substituted glycine-.butyl esterds obtained inthe usual man.- ner,,startingjwith a-naphthylamine. l-a-naphthyl-2-mercapto-5-carbobutoxyimidazole melts at ab0ut16l166 C.

EXAMPLE 8 Preparation of z-mercapto-5-carbohearyloacyimz'dazole 2L mercapto 5 carbohexyloxyimidazole represented by the formula HC:CC.O O C sHia is prepared according. to thepmcedureof .Example..1, from sodium .thiocyanate and the. salt of ,the C-formyl derivative of. the. hexyl .ester of is prepared'according .to the procedure of Examp19 1, from sodium thiocyanateandthe sodium salt of the C -for'myl derivative of N-ptolyl-N- formylglycine allyl ester." N -p-to'lyl' N-formyl-C- formylglyc ine allyl ester is obtained by reacting p-toluidinefand chloroacetic acid to 'give N -ptolylglycine, and esterifyin'g and formylating the N" p t'olylglycine'. 1 p -tolyl 2 mercapto- 5-oarballyloxyimidazole melts at about 183 Preparation of 1 phenethyl 2 mercapto 5- carbethoxyimidazoZe 1 phenethyl 2- mercapto 5 carbethoxyirnidazole represented by the formula is prepared according to the. .procedure.of.Exam- Preparation of 1-cycZopentyl-2-mercapto-5-carbomethoryimidazole 1 cyclopentyl '2 mercapto 5 carbometh oxyimidazole represented by the formula Hc=-oooo11 cnhcn2 N NC is prepared according to the procedure of Example 2, from thiocyanic acid and the C-formyl derivative of N cyclohexyl N formylglycine methyl ester. The glycine derivative is obtained by reacting cyclopentylamine with formaldehyde and hydrocyanic acid followed by hydrolysis, esterification and formylation in the usual manner. 1 cyclopentyl 2 -.mercapto 5 carbomethoxyimidazole melts at about 167-169 C.

EXAMPLE 12 Preparatz'dn of I-phenyl 2 mercapto carbomethoxyimzdazole 1 phenyl 2 mercapto 5 carbomethoxyimidazole represented by the formula EXANIPLE 13 Preparation of 1- phenyl 2 :mercapto 5- carbethoryimidazole 1 phenyl 2 mercapto 5 carbethoxyimidazole represented by the formula is prepared by a method analogous to that employed in the preparation of the 1-phenyl-2- mercapto-5-carbomethoxyimidazole of Example 12, starting with the C-formyl derivative of N-phenyl-N-a'cetylglycine ethyl ester. l-phenyl- 2 mercapto 5 carbethoxyimidazole melts at about 188190 C. Analysis has shown the presence of 11.43 percent nitrogen as compared with calculated value of 11.28 percent nitrogen.

.10 EXAMPLE 14 Preparation of 1-dodecyZ-2-mercapto-5-carbomethoasyimidazole 1 dodecyl 2 mercapto 5 carbomethoxyimidazole represented by the formula HC=CCOOCH3 I SE is prepared according to the procedure of Example 1, from sodium thiocyanate and the sodium salt of the C-formylderivative of N-dodecyl-N- formylglycine methyl ester. The substituted glycine derivative is obtained in the usual manner, starting with dodecyl amine. mercapto 5 carbomethoxyimidazole melts at about 98-100 C.

I claim:

1. A method of preparing a 2-mercapto-5- carboxyimidazole ester which comprises condensing a C-formylglycine ester enol with a thiocyanate.

2. A method of preparing a 2-mercapto-5- carboxyimidazole ester having the following formula TO A wherein R represents a member of the group consisting of hydrogen, alkyl, cycloalkyl, aryl and alphyl, and R1 represents a lower aliphatic esterifying radical, said method comprising condensing in aqueous solution a thiocyanate with a C-formylglycine ester enol having the following formula wherein R and R1 have the same significance as before and R2 represents a member of the group consisting of hydrogen, methyl and ethyl.

3. A method according to claim 2 in which the thiocyanate is thiocyanic acid.

4. A method according to claim 2 in which the thiocyanate is a, water-soluble metal thiocyanate and the condensation is carried out in the presence of a strong, non-oxidizing mineral acid.

5. A method according to claim 2 in which the thiocyanate is in the form of a water-soluble metal salt and the condensation is carried out in the presence of a strong, non-oxidizing mineral acid.

'6. A method of preparing a 2-mercapto-5- carboxyimidazole ester, which comprises condensing in aqueous solution at a temperature between about 20 C. and 100 C. a thiocyanate and a C-formylglycine ester enol. represented by the formula Rz-( '!l 1'(I7'COOR1 hHOH wherein R is a member of the group consisting of hydrogen, alkyl, cycloalkyl, aryl and alphyl,

1-dodecyl-2-' 12 carboxyimidazole ester having the following 1 'REFERENCES CITED formula jl i e 'following references are" of record in the 7 filerofrthis patent1: 7 H 1 5 7 FOREIGN-.BA'IZENTS Niirnbe'f 'cafifitry nate 5 B 258,296 Germany Apifii, 1913 wherein R represents a,: member of the group consisting of hydrogen," arm, cycloalkyl, aryl r and alphyl, and R1 represents a lower aliphatic 'Bei l stin;' ith rdj'ivo1.'25; ;1ie5g 216 (1935)B'0th esterifying radical, said method comprising bringreferring to: Gabriel and Posner, Ber. Deut. ing together xin rgnaqueous:solution at a tern: ChemnGeseH ;vo1= 27.(1894);pages 1141 fi.-

per-ature;.between;.a pont fififl nc1 1;( )0 C- 1a Coghillz Penicillin .z-Report .:6,..Apri12,1, .1944; .thiocyanaterand fiaCzfOT-IQYZQY e-rest erenql; CPS #182 (10 pages,.-e speciallyzpage 4).

JONES; 

1. A METHOD OF PREPARING A 2-MERCAPTO-5CARBOXYIMIDAZOLE ESTER WHICH COMPRISES CONDENSING A C-FORMYLGLYCINE ESTER ENOL WITH A THIOCYANATE. 